molecules Article Iron-Catalysed C(sp2)-H Borylation Enabled by Carboxylate Activation Luke Britton 1, Jamie H. Docherty 1,*, Andrew P. Dominey 2 and Stephen P. Thomas 1,* 1 EaStCHEM School of Chemistry, University of Edinburgh, Joseph Black Building, David Brewster Road, Edinburgh EH9 3FJ, UK; [email protected] 2 GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK; [email protected] * Correspondence: [email protected] (J.H.D.); [email protected] (S.P.T.) Received: 30 January 2020; Accepted: 14 February 2020; Published: 18 February 2020 Abstract: Arene C(sp2)-H bond borylation reactions provide rapid and efficient routes to synthetically versatile boronic esters. While iridium catalysts are well established for this reaction, the discovery and development of methods using Earth-abundant alternatives is limited to just a few examples. Applying an in situ catalyst activation method using air-stable and easily handed reagents, the iron-catalysed C(sp2)-H borylation reactions of furans and thiophenes under blue light irradiation have been developed. Key reaction intermediates have been prepared and characterised, and suggest two mechanistic pathways are in action involving both C-H metallation and the formation of an iron boryl species. Keywords: catalysis; borylation; Iron; C-H functionalisation; pinacolborane; photochemistry 1. Introduction The development of sustainable methods for the selective C(sp2)-H functionalisation of arenes is an area of intense research but is still dominated by the use of 2nd- and 3rd-row transition metals [1–7]. Earth-abundant metals offer low toxicity and inexpensive alternatives, with iron being a leading example [8–12]. Direct C(sp2)-H borylation offers a simple and efficient route to aryl-boronic esters, which are key platforms for organic synthesis [13–15]. Iridium-based complexes have become a “go-to” for C(sp2)-H borylation reactions [16–24], while the discovery and development of Earth-abundant alternatives remains comparatively rare [25–37]. Tatsumi and Ohki showed that arenes would undergo thermally promoted C(sp2)-H borylation using an N-heterocyclic carbene cyclopentadienyl iron(II) alkyl complex [NHC(Cp*)FeMe] as a catalyst in the presence of tert-butylethylene (Scheme1a) [ 35]. Mankad applied heterobimetallic Fe-Cu and Fe-Zn complexes under continuous ultraviolet light irradiation to arene C(sp2)-H borylation [36]. Similarly, Darcel and co-workers reported the use of a bis(diphosphino) iron(II) dialkyl and dihydride complexes for arene C(sp2)-H borylation, again under continuous ultraviolet light irradiation [37]. While these landmark reports are highly significant developments, all require the prior synthesis of sensitive inorganic complexes which are synthetically challenging and difficult to handle for the non-specialist practitioner, thus limiting use by the broader synthetic community. Molecules 2020, 25, 905; doi:10.3390/molecules25040905 www.mdpi.com/journal/molecules Molecules 2020, 25, 905 2 of 11 Molecules 2020, 25, x FOR PEER REVIEW 2 of 12 SchemeScheme 1. Iron-catalysed 1. Iron-catalysed C-H C-H borylation borylation of arenes.of arenes. (a )(a Prior) Prior approaches approaches to to iron-catalysed iron-catalysed C( C(spsp22)-H-bond)-H- borylationbond borylation with pinacolborane with pinacolborane (HBpin) (HBpin) using organoiron using organoiron and iron and/copper iron/copper bimetallic bimetallic catalysts. catalysts. (b) This (b) This 2work: C(sp2)-H bond borylation using dmpe2FeCl2 as a pre-catalyst, activated by exogenous work: C(sp )-H bond borylation using dmpe2FeCl2 as a pre-catalyst, activated by exogenous nucleophiles, under blue light irradiation. nucleophiles, under blue light irradiation. To reduce the synthetic challenges, and need for organometallic reagents, we questioned To reduce the2 synthetic challenges, and need for organometallic reagents, we questioned whether the C(2sp )-H borylation chemistry reported previously could be simplified by in situ catalyst whetheractivation the C(usingsp )-H only borylation bench stable chemistry reagents. In reported the example previously reported by could Darcel be and simplified co-workers by the in situ catalystbis[1,2-bis(dimethylphosphino)ethane- activation using only bench stableP,P′]dimethyliron(II) reagents. In thepre-catalyst example reported(dmpe2FeMe by2) Darcelwas and co-workersgenerated the by bis[1,2-bis(dimethylphosphino)ethane- the addition of methyllithium to theP ,Pcorresponding0]dimethyliron(II) iron(II) pre-catalyst dichloride (dmpe complex2FeMe 2) was generated(dmpe2FeCl2 by) [37]. the additionSimilarly, of methyllithiumthe catalytically to active the corresponding bis[1,2-bis(dimethylphosphino)ethane- iron(II) dichloride complex (dmpeP,2PFeCl′]iron(II)2)[37 dihydride]. Similarly, (dmpe the2FeH catalytically2) could be active accessed bis[1,2-bis(dimethylphosphino)ethane- using either LiHBEt3 or LiAlH4 [37,38].P Given,P0]iron(II) our previous work on the in situ generation of hydride donors formed by the combination of alkoxide dihydride (dmpe2FeH2) could be accessed using either LiHBEt3 or LiAlH4 [37,38]. Given our previous worksalts on theand inpinacolborane situ generation (HBpin) of hydride[39], we postulated donors formed that the by active the combinationC(sp2)-H borylation of alkoxide pre-catalyst, salts and dmpe2FeH2, may be accessible by the same method. Reaction of2 substoichiometric alkoxide salt with pinacolborane (HBpin) [39], we postulated that the active C(sp )-H borylation pre-catalyst, dmpe2FeH2, HBpin, the boron source used for this borylation, would generate a hydride reductant in situ to may be accessible by the same method. Reaction of substoichiometric alkoxide salt with HBpin, the activate the dmpe2FeCl2 pre-catalyst to dmpe2FeH2, the active borylation catalyst, and thus initiate boron source used for this borylation, would generate a hydride reductant in situ to activate the catalysis. Importantly, the dmpe2FeCl2 complex displays much greater air- and moisture stability dmpecompared2FeCl2 pre-catalyst to the dihydride to dmpe and2 FeHdialkyl2, theanalogues. active borylationHerein, we catalyst,report the and in thussitu activation initiate catalysis. of Importantly,dmpe2FeCl the2 and dmpe application2FeCl2 complexto the C(sp displays2)-H borylation much reaction greater of air- heteroarenes and moisture (Scheme stability 1b). compared to the dihydride and dialkyl analogues. Herein, we report the in situ activation of dmpe2FeCl2 and application2. Results to the C(sp2)-H borylation reaction of heteroarenes (Scheme1b). Guided by the work of Darcel and co-workers, we selected 2-methylfuran 2a as an ideal test 2. Results substrate for our investigations. Darcel and co-workers showed that dmpe2FeMe2 could be used as a Guidedpre-catalyst by for the the work borylation of Darcel of andfuran co-workers, 2a (3 equiv.) we using selected HBpin 2-methylfuran (1 equiv.) under2a ascontinuous an ideal test substrate for our investigations. Darcel and co-workers showed that dmpe FeMe could be used as a 2 2 pre-catalyst for the borylation of furan 2a (3 equiv.) using HBpin (1 equiv.) under continuous ultraviolet light irradiation to give a regioisomeric mixture of 5- and 4-borylated furans, 3a and 4a respectively Molecules 2020, 25, 905 3 of 11 Molecules 2020, 25, x FOR PEER REVIEW 3 of 12 (67%,ultraviolet3a:4a = 82:18) light irradiation [37]. Using to ourgive alkoxide a regioisomeric activation mixture strategy of 5- we and found 4-borylated the use furans, of ultraviolet 3a and 4a light for thisrespectively reaction was (67%, not necessary,3a:4a = 82:18) instead [37]. operatingUsing our alkoxide with lower activation energy strategy blue light we (Kessil found A160the use WE, of 40 W Blueultraviolet LED). Additionally, light for this we reaction used anwas inverted not necessar stoichiometryy, instead operating of arene with (1 equiv.) lower andenergy HBpin blue (1.2light equiv) and(Kessil a reduced A160 catalyst WE, 40 W loading. Blue LED). Using Additionally, these reaction we us parameters,ed an inverted we stoichiometry assessed the of arene ability (1 ofequiv.) a selection and HBpin (1.2 equiv) and a reduced catalyst loading. Using these reaction parameters, we assessed of potential activators to initiate catalysis alongside the dmpe2FeCl2 1 pre-catalyst. (Scheme2). the ability of a selection of potential activators to initiate catalysis alongside the dmpe2FeCl2 1 pre- Any of LiOMe, KOMe, TBAOMe (TBA = tetra-n-butylammonium), NaOiPr, NaOtBu or KOtBu catalyst. (Scheme 2). triggeredAny pre-catalyst of LiOMe, activationKOMe, TBAOMe and the (TBA formation = tetra-n of-butylammonium), both furyl boronic NaO esteriPr, NaO regioisomers,tBu or KOtBu3a and 4a, albeittriggered in modestpre-catalyst yields activation (17% and to 39%) the format and withion of varying both furyl regioselectivity, boronic ester regioisomers, after 24 h. 3a The and use of carboxylate4a, albeit salts in modest also initiated yields (17% catalysis; to 39%) NaO and2CH, with LiOAc, varying NaOAc, regioselectivity, Na(2-EH) after (2-EH 24= h.2-ethylhexanoate), The use of TBA(2-EH),carboxylate NaO salts2CPh, also NaO initiated2CCF3 allcatalysis; successfully NaO2CH, initiated LiOAc, catalysis NaOAc, with Na(2-EH) varying (2-EH efficiency = 2- (2% to 45%).ethylhexanoate), Na(2-EH) and TBA(2-EH), NaO2CPh NaO outperformed2CPh, NaO2CCF all alkoxide3 all successfully salts, and initiated the yields catalysis obtained with varying using these activatorsefficiency could (2% be to